Tang Soon Yew, Monslow James, R Grant Gregory, Todd Leslie, Pawelzik Sven-Christian, Chen Lihong, Lawson John, Puré Ellen, FitzGerald Garret A
From Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Department of Systems Pharmacology and Translational Therapeutics (S.Y.T., J.M., L.T., S.-C.P., L.C., E.P., G.A.F.); Department of Animal Biology, School of Veterinary Medicine (S.Y.T., G.R.G., J.L.); and Department of Genetics, University of Pennsylvania, Philadelphia (J.M.).
Circulation. 2016 Jul 26;134(4):328-38. doi: 10.1161/CIRCULATIONAHA.116.022308.
Inhibitors of cyclooxygenase-2 alleviate pain and reduce fever and inflammation by suppressing the biosynthesis of prostacyclin (PGI2) and prostaglandin E2. However, suppression of these prostaglandins, particularly PGI2, by cyclooxygenase-2 inhibition or deletion of its I prostanoid receptor also predisposes to accelerated atherogenesis and thrombosis in mice. By contrast, deletion of microsomal prostaglandin E synthase 1 (mPGES-1) confers analgesia, attenuates atherogenesis, and fails to accelerate thrombogenesis, while suppressing prostaglandin E2, but increasing biosynthesis of PGI2.
To address the cardioprotective contribution of PGI2, we generated mice lacking the I prostanoid receptor together with mPges-1 on a hyperlipidemic background (low-density lipoprotein receptor knockouts).
mPges-1 depletion modestly increased thrombogenesis, but this response was markedly further augmented by coincident deletion of the I prostanoid receptor (n=10-18). By contrast, deletion of the I prostanoid receptor had no effect on the attenuation of atherogenesis by mPGES-1 deletion in the low-density lipoprotein receptor knockout mice (n=17-21).
Although suppression of prostaglandin E2 accounts for the protective effect of mPGES-1 deletion in atherosclerosis, augmentation of PGI2 is the dominant contributor to its favorable thrombogenic profile. The divergent effects on these prostaglandins suggest that inhibitors of mPGES-1 may be less likely to cause cardiovascular adverse effects than nonsteroidal anti-inflammatory drugs specific for inhibition of cyclooxygenase-2.
环氧合酶-2抑制剂通过抑制前列环素（PGI2）和前列腺素E2的生物合成来减轻疼痛、降低发热和炎症。然而，通过环氧合酶-2抑制或其IP前列腺素受体缺失来抑制这些前列腺素，尤其是PGI2，也会使小鼠更容易发生动脉粥样硬化和血栓形成加速。相比之下，微粒体前列腺素E合酶1（mPGES-1）的缺失可产生镇痛作用，减轻动脉粥样硬化，且在抑制前列腺素E2的同时增加PGI2的生物合成，不会加速血栓形成。
为了研究PGI2的心脏保护作用，我们构建了在高脂血症背景下（低密度脂蛋白受体敲除小鼠）同时缺乏IP前列腺素受体和mPges-1的小鼠。
mPges-1缺失适度增加了血栓形成，但IP前列腺素受体的同时缺失会使这种反应明显进一步增强（n = 10 - 18）。相比之下，在低密度脂蛋白受体敲除小鼠中，IP前列腺素受体的缺失对mPGES-1缺失减轻动脉粥样硬化没有影响（n = 17 - 21）。
虽然前列腺素E2的抑制解释了mPGES-1缺失在动脉粥样硬化中的保护作用，但PGI2的增加是其有利血栓形成特征的主要促成因素。对这些前列腺素的不同影响表明，与特异性抑制环氧合酶-2的非甾体抗炎药相比，mPGES-1抑制剂可能不太可能引起心血管不良反应。
